tbuckley/cabot-search huggingface dataset:
IL-6 selectively suppresses cDC1 specification via C/EBPβ
Authors: Sunkyung Kim, Jing Chen, Suin Jo, Feiya Ou, Stephen T. Ferris, Tian-Tian Liu, Ray A. Ohara, David A. Anderson, Renee Wu, Michael Y. Chen, William E. Gillanders, William E. Gillanders, Theresa L. Murphy, Kenneth M. Murphy
Journal: The Journal of Experimental Medicine (2023)

Cytokines produced in association with tumors can impair antitumor immune responses by reducing the abundance of type 1 conventional dendritic cells (cDC1), but the mechanism remains unclear. Here, we show that tumor-derived IL-6 generally reduces cDC development but selectively impairs cDC1 development in both murine and human systems through the induction of C/EBPβ in the common dendritic cell progenitor (CDP). C/EBPβ and NFIL3 compete for binding to sites in the Zeb2 −165 kb enhancer and support or repress Zeb2 expression, respectively. At homeostasis, pre-cDC1 specification occurs upon Nfil3 induction and consequent Zeb2 suppression. However, IL-6 strongly induces C/EBPβ expression in CDPs. Importantly, the ability of IL-6 to impair cDC development is dependent on the presence of C/EBPβ binding sites in the Zeb2 −165 kb enhancer, as this effect is lost in Δ1+2+3 mutant mice in which these binding sites are mutated. These results explain how tumor-associated IL-6 suppresses cDC1 development and suggest therapeutic approaches preventing abnormal C/EBPβ induction in CDPs may help reestablish cDC1 development to enhance antitumor immunity.
A Review of Glioblastoma and Other Primary Brain Malignancies—Reply
Authors: Lauren R. Schaff, Ingo K. Mellinghoff
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Association of Hospital Incentive Care Management Partnerships for Uninsured Patients With Emergency Department Utilization
Authors: Sarah Gareau, Ana López-De Fede, Zhimin Chen, Nathaniel Bell, Kathy Mayfield-Smith
Journal: JAMA Network Open (2023)

Importance The South Carolina (SC) Healthy Outcomes Plan (HOP) program aimed to expand access to health care to individuals without insurance; it remains unknown whether there is an association between the SC HOP program and emergency department (ED) use among patients with high health care costs and needs. Objectives To determine whether participation in the SC HOP was associated with reduced ED utilization among uninsured participants. Design, Setting, and Participants This retrospective cohort study included 11 684 HOP participants (ages 18-64 years) with at least 18 months of continuous enrollment. Generalized estimating equations and segmented regression of interrupted time-series analyses of ED visits and charges were conducted from October 1, 2012, to March 31, 2020. Exposures Time intervals related to the HOP were 1 year before and 3 years after participation. Main Outcomes and Measures ED visits per 100 participants per month and ED charges per participant per month overall and by subcategory. Results The mean (SD) age of the 11 684 participants in the study was 45.2 (10.9) years; 6293 (54.5%) were women; 5028 (48.4%) were Black participants and 5189 (50.0%) were White participants. Over the study period, the mean (SE) number of ED visits decreased by 44.1%, from 48.1 (5.2) to 26.9 (2.8) per 100 participants per month. The mean (SE) ED charges were reduced to $858 ($46) per participant per month, a decrease from a mean (SE) of $1583 ($88) per participant per month 1 year before HOP implementation. There was an immediate level decrease of 40% (relative risk [RR], 0.61; 99.5% CI, 0.48-0.76; P &amp;amp;lt; .001) from the preenrollment period, with a sustained reduction trend of 8% (RR 0.92; 99.5% CI, 0.89-0.95; P &amp;amp;lt; .001) during the postenrollment period. A level change for ED charges was detected, at a decrease of 40% (RR 0.60; 99.5% CI, 0.47-0.77; P &amp;amp;lt; .001) directly after HOP enrollment with a subsequent downward trend of 10% (RR 0.90; 99.5% CI, 0.86-0.93; P &amp;amp;lt; .001) for the postenrollment period. Conclusions and Relevance In this retrospective cohort study, proportions and charges of ED visits by uninsured patients saw immediate and sustained decreases after HOP enrollment. Reducing ED charges may have been driven by decreasing the ED as the primary point of patient care, especially for high-frequency users. These findings have implications for other nonexpansion states seeking to maximize uninsured compensation for low-income populations through improved outcomes.
Is Immunotherapy With Concomitant Proton Pump Inhibitor Use a Viable Combination?
Authors: Alessio Stefani, Emilio Bria
Journal: JAMA Network Open (2023)

Hayato Kawachi, MD; Tadaaki Yamada, MD, PhD; Motohiro Tamiya, MD; Yoshiki Negi, MD, PhD; Yasuhiro Goto, MD, PhD; Akira Nakao, MD; Shinsuke Shiotsu, MD, PhD; Keiko Tanimura, MD, PhD; Takayuki Takeda, MD, PhD; Asuka Okada, MD, PhD; Taishi Harada, MD; Koji Date, MD; Yusuke Chihara, MD, PhD; Isao Hasegawa, MD, PhD; Nobuyo Tamiya, MD, PhD; Masaki Ishida, MD; Yuki Katayama, MD; Kenji Morimoto, MD, PhD; Masahiro Iwasaku, MD, PhD; Shinsaku Tokuda, MD, PhD; Takashi Kijima, MD, PhD; Koichi Takayama, MD, PhD
Rapid Reduction of HbA1c and Early Worsening of Diabetic Retinopathy: A Real-world Population-Based Study in Subjects With Type 2 Diabetes
Authors: Rafael Simó, Josep Franch-Nadal, Bogdan Vlacho, Jordi Real, Ester Amado, Juana Flores, Manel Mata-Cases, Emilio Ortega, Mercedes Rigla, Joan-Anton Vallés, Cristina Hernández, Didac Mauricio
Journal: Diabetes Care (2023)

OBJECTIVE Early worsening of diabetic retinopathy (EWDR) due to the rapid decrease of blood glucose levels is a concern in diabetes treatment. The aim of the current study is to evaluate whether this is an important issue in subjects with type 2 diabetes with mild or moderate nonproliferative DR (NPDR), who represent the vast majority of subjects with DR attended in primary care. RESEARCH DESIGN AND METHODS This is a retrospective nested case-control study of subjects with type 2 diabetes and previous mild or moderate NPDR. Using the SIDIAP (“Sistema d'informació pel Desenvolupament de la Recerca a Atenció Primària”) database, we selected 1,150 individuals with EWDR and 1,150 matched control subjects (DR without EWDR). The main variable analyzed was the magnitude of the reduction of HbA1c in the previous 12 months. The reduction of HbA1c was categorized as rapid (&amp;gt;1.5% reduction in &amp;lt;12 months) or very rapid (&amp;gt;2% in &amp;lt;6 months). RESULTS We did not find any significant difference in HbA1c reduction between case and control subjects (0.13 ± 1.21 vs. 0.21 ± 1.18; P = 0.12). HbA1c reduction did not show significant association with worsening of DR, neither in the unadjusted analyses nor in adjusted statistical models that included the main confounding variables: duration of diabetes, baseline HbA1c, presence of hypertension, and antidiabetic drugs. In addition, when stratification by baseline HbA1c was performed, we did not find that those patients with higher levels of HbA1c presented a higher risk to EWDR. CONCLUSIONS Our results suggest that the rapid reduction of HbA1c is not associated with progression of mild or moderate NPDR.
Allosteric modulator potentiates β2AR agonist–promoted bronchoprotection in asthma models
Authors: Seungkirl Ahn, Harm Maarsingh, Julia K.L. Walker, Samuel Liu, Akhil Hegde, Hyeje C. Sumajit, Alem W. Kahsai, Robert J. Lefkowitz
Journal: Journal of Clinical Investigation (2023)

Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote - with limited efficacy - bronchodilation in asthma. All β2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine. We recently isolated a β2AR-selective positive allosteric modulator (PAM), compound-6 (Cmpd-6), which binds outside of the orthosteric site and modulates orthosteric ligand functions. With the emerging therapeutic potential of G-protein coupled receptor allosteric ligands, we investigated the impact of Cmpd-6 on β2AR-mediated bronchoprotection. Consistent with our findings using human β2ARs, Cmpd-6 allosterically potentiated β2-agonist binding to guinea pig β2ARs and downstream signaling of β2ARs. In contrast, Cmpd-6 had no such effect on murine β2ARs, which lack a crucial amino acid in the Cmpd-6 allosteric binding site. Importantly, Cmpd-6 enhanced β2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in guinea pig lung slices, but - in line with the binding studies - not in mice. Moreover, Cmpd-6 robustly potentiated β2 agonist-mediated bronchoprotection against allergen-induced airway constriction in lung slices obtained from a guinea pig model of allergic asthma. Cmpd-6 similarly enhanced β2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in human lung slices. Our results highlight the potential of β2AR-selective PAMs in the treatment of airway narrowing in asthma and other obstructive respiratory diseases.
Association Between Historical Neighborhood Redlining and Cardiovascular Outcomes Among US Veterans With Atherosclerotic Cardiovascular Diseases
Authors: Salil V. Deo, Issam Motairek, Khurram Nasir, Amgad Mentias, Yakov Elgudin, Salim S. Virani, Sanjay Rajagopalan, Sadeer Al-Kindi
Journal: JAMA Network Open (2023)

In the 1930s, the government-sponsored Home Owners' Loan Corporation (HOLC) established maps of US neighborhoods that identified mortgage risk (grade A [green] characterizing lowest-risk neighborhoods in the US through mechanisms that transcend traditional risk factors to grade D [red] characterizing highest risk). This practice led to disinvestments and segregation in neighborhoods considered redlined. Very few studies have targeted whether there is an association between redlining and cardiovascular disease.
Advancing therapeutics for recurrent clostridioides difficile infections: an overview of vowst’s FDA approval and implications
Authors: Nityanand Jain, Tungki Pratama Umar, Anne-Fleur Fahner, Valdis Gibietis
Journal: Gut Microbes (2023)

Clostridioides difficile infections (CDI) are a leading cause of healthcare-associated infections with a high relapse rate. Current treatment guidelines recommend fidaxomicin as the primary therapy for initial CDI episodes and suggest alternative approaches for recurrent episodes, including fecal microbiota transplantation (FMT). This paper explores the recent approval of Vowst, a novel oral FMT drug, by the United States Food and Drug Administration (FDA) as a prophylactic therapy to prevent recurrent CDIs. Vowst comprises a formulation of live fecal microbiota spores and works by reestablishing the disrupted gut microbiota, limiting C. difficile spore germination, and promoting microbiome repair. Furthermore, this paper will discuss the product's approval journey and the uncertainties regarding its efficacy in CDI patients beyond the ones who participated in the clinical trials, pharmacovigilance, cost estimates, and the need for a more stringent donor screening process. Overall, Vowst's approval marks a significant step forward in the prevention of recurrent CDI infections with various beneficial implications for future gastroenterology.
Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis
Authors: Deepika Awasthi, Sahil Chopra, Byuri A. Cho, Alexander Emmanuelli, Tito A. Sandoval, Sung-Min Hwang, Chang-Suk Chae, Camilla Salvagno, Chen Tan, Liliana Vasquez-Urbina, Jose J. Fernandez Rodriguez, Sara F. Santagostino, Takao Iwawaki, E. Alfonso Romero-Sandoval, Mariano Sanchez Crespo, Diana K. Morales, Iliyan D. Iliev, Tobias M. Hohl, Juan R. Cubillos-Ruiz
Journal: Journal of Clinical Investigation (2023)

Recognition of pathogen-associated molecular patterns can trigger the inositol-requiring enzyme 1 α (IRE1α) arm of the endoplasmic reticulum (ER) stress response in innate immune cells. This process maintains ER homeostasis and also coordinates diverse immunomodulatory programs during bacterial and viral infections. However, the role of innate IRE1α signaling in response to fungal pathogens remains elusive. Here, we report that systemic infection with the human opportunistic fungal pathogen Candida albicans induced proinflammatory IRE1α hyperactivation in myeloid cells that led to fatal kidney immunopathology. Mechanistically, simultaneous activation of the TLR/IL-1R adaptor protein MyD88 and the C-type lectin receptor dectin-1 by C. albicans induced NADPH oxidase-driven generation of ROS, which caused ER stress and IRE1α-dependent overexpression of key inflammatory mediators such as IL-1β, IL-6, chemokine (C-C motif) ligand 5 (CCL5), prostaglandin E2 (PGE2), and TNF-α. Selective ablation of IRE1α in leukocytes, or treatment with an IRE1α pharmacological inhibitor, mitigated kidney inflammation and prolonged the survival of mice with systemic C. albicans infection. Therefore, controlling IRE1α hyperactivation may be useful for impeding the immunopathogenic progression of disseminated candidiasis.
DNA Sequencing in Adults With Acute Myeloid Leukemia to Detect Residual Disease Prior to Hematopoietic Cell Transplant
Authors: Niranjan Shiwaji Khaire, Dennis Dong Hwan Kim, Arjun D. Law
Journal: JAMA (2023)

To the Editor A recent study1 showed pretransplant persistence of FLT3 internal tandem duplication (FLT3-ITD) and NPM1 variants in adults with acute myeloid leukemia (AML) to be an effective predictor of posttransplant relapse. We have several observations about this study.
Optical Approaches for Investigating Neuromodulation and G Protein–Coupled Receptor Signaling
Authors: David J. Marcus, Michael R. Bruchas
Journal: Pharmacological Reviews (2023)

Despite the fact that roughly 40% of all US Food and Drug Administration (FDA)-approved pharmacological therapeutics target G protein–coupled receptors (GPCRs), there remains a gap in our understanding of the physiologic and functional role of these receptors at the systems level. Although heterologous expression systems and in vitro assays have revealed a tremendous amount about GPCR signaling cascades, how these cascades interact across cell types, tissues, and organ systems remains obscure. Classic behavioral pharmacology experiments lack both the temporal and spatial resolution to resolve these long-standing issues. Over the past half century, there has been a concerted effort toward the development of optical tools for understanding GPCR signaling. From initial ligand uncaging approaches to more recent development of optogenetic techniques, these strategies have allowed researchers to probe longstanding questions in GPCR pharmacology both in vivo and in vitro. These tools have been employed across biologic systems and have allowed for interrogation of everything from specific intramolecular events to pharmacology at the systems level in a spatiotemporally specific manner. In this review, we present a historical perspective on the motivation behind and development of a variety of optical toolkits that have been generated to probe GPCR signaling. Here we highlight how these tools have been used in vivo to uncover the functional role of distinct populations of GPCRs and their signaling cascades at a systems level. <h3>Significance Statement</h3> G protein–coupled receptors (GPCRs) remain one of the most targeted classes of proteins for pharmaceutical intervention, yet we still have a limited understanding of how their unique signaling cascades effect physiology and behavior at the systems level. In this review, we discuss a vast array of optical techniques that have been devised to probe GPCR signaling both in vitro and in vivo.
Intrapartum Azithromycin vs Placebo for Neonatal Sepsis
Authors: Wan-Jie Gu, Jun Lyu, Hai-Yan Yin
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Mathematical modelling of microneedle-mediated transdermal delivery of drug nanocarriers into skin tissue and circulatory system
Authors: Ben Newell, Wenbo Zhan
Journal: Journal of Controlled Release (2023)

Microneedle-mediated transdermal delivery using nanocarriers can successfully overcome the barrier of the stratum corneum and protect drugs from elimination in skin tissues. However, the effectiveness of drug delivery to different layers of skin tissues and the circulatory system varies considerably, subject to the properties of the drug delivery system and delivery regime. How to maximise delivery outcomes remains unclear. In this study, mathematical modelling is employed to investigate this transdermal delivery under various conditions, using the skin model that is reconstructed based on the realistic skin anatomical structure. Treatment efficacy is evaluated in terms of drug exposure over time. The modelling results demonstrate the complex dependence of drug accumulation and distribution on the nanocarrier properties, microneedle properties and environment in different skin layers and blood. Specifically, delivery outcomes in the entire skin and blood can be improved by increasing the loading dose and reducing microneedle spacing. However, several parameters need to be optimised with respect to the specific location of the target site in the tissue for better treatment; these include the drug release rate, nanocarrier diffusivity in microneedle and skin tissue, nanocarrier transvascular permeability, nanocarrier partition coefficient between tissue and microneedle, microneedle length, wind speed and relative humidity. The delivery is less sensitive to the diffusivity and physical degradation rate of free drugs in microneedle, and their partition coefficient between tissue and microneedle. Results obtained from this study can be used to improve the design of the microneedle-nanocarrier combined drug delivery system and delivery regime.
Patterns of US Mental Health–Related Emergency Department Visits During the COVID-19 Pandemic
Authors: Sofia Villas-Boas, Scott Kaplan, Justin S. White, Renee Y. Hsia
Journal: JAMA Network Open (2023)

Numerous studies have shown that the prevalence of mental health (MH) conditions worsened during the COVID-19 pandemic. Further research is needed on this phenomenon over a longer time horizon that considers the increasing trend in MH conditions before the pandemic, after the pandemic onset, and after vaccine availability in 2021.To track how patients sought help in emergency departments (EDs) for non-MH and MH conditions during the pandemic.This cross-sectional study used administrative data on weekly ED visits and a subset of visits for MH from the National Syndromic Surveillance Program from January 1, 2019, to December 31, 2021. Data were reported from the 10 US Department of Health and Human Services (HHS) regions (Boston, New York, Philadelphia, Atlanta, Chicago, Dallas, Kansas City, Denver, San Francisco, and Seattle) for five 11-week periods. Data analysis was performed in April 2023.Weekly trends in total ED visits, mean MH-related ED visits, and proportion of ED visits for MH conditions were investigated to determine changes in each measure after the pandemic onset. Prepandemic baseline levels were established from 2019 data, and time trends of these patterns were examined in the corresponding weeks of 2020 and 2021. A fixed-effects estimation approach with weekly ED region data by year was used.There were 1570 total observations in this study (52 weeks in 2019, 53 weeks in 2020, and 52 weeks in 2021). Statistically significant changes in non-MH and MH-related ED visits were observed across the 10 HHS regions. The mean total number of ED visits decreased by 45 117 (95% CI, -67 499 to -22 735) visits per region per week (39% decrease; P = .003) in the weeks after the pandemic onset compared with corresponding weeks in 2019. The mean number of ED visits for MH conditions (-1938 [95% CI, -2889 to -987]; P = .003) decreased significantly less (23% decrease) than the mean number of total visits after the onset of the pandemic, increasing the mean (SD) proportion of MH-related ED visits from 8% (1%) in 2019 to 9% (2%) in 2020. In 2021, the mean (SD) proportion decreased to 7% (2%), and the mean number of total ED visits rebounded more than that of mean MH-related ED visits.In this study, MH-related ED visits demonstrated less elasticity than non-MH visits during the pandemic. These findings highlight the importance of addressing the provision of adequate MH services, both in acute and outpatient settings.
Historical Structural Barriers and Cardiovascular Inequities
Authors: Colleen A. Burke, Hayden B. Bosworth
Journal: JAMA Network Open (2023)

Salil V. Deo, MD; Issam Motairek, MD; Khurram Nasir, MD, MSc; Amgad Mentias, MD; Yakov Elgudin, MD, PhD; Salim S. Virani, MD, PhD; Sanjay Rajagopalan, MD; Sadeer Al-Kindi, MD